Published on Web 06/05/2003
Catalytic Enone Cycloallylation via Concomitant Activation of Latent Nucleophilic and Electrophilic Partners: Merging Organic and Transition Metal Catalysis Bradley G. Jellerichs, Jong-Rock Kong, and Michael J. Krische* UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712 Received March 3, 2003; E-mail:
[email protected] Modular design of catalytic transformations based on the use of enones as latent enolates is currently under development in our lab.1 Through variation of the method of enone nucleophilic activation (hydrometalation, carbometalation or nucleophilic organocatalysis), coupled with the use of diverse electrophilic partners, a family of catalytic cycloreductions,2 cycloadditions3 and cycloisomerizations4 has emerged. While use of “classical” electrophilic partners such as appendant aldehydes, ketones and enones has been demonstrated,1-4 an opportunity for further development resides in catalytic couplings to “nonclassical” electrophiles, such as allylic carbonates. The use of allylic carbonates as latent electrophiles mandates activation via metallo-π-allyl formation. In this regard, palladium complexes have proven especially effective.5 The compatibility of palladium-based catalysts and tertiary phosphines suggests the feasibility of catalytic enone allylation processes, whereby activation of latent nucleophilic (enone) and electrophilic (allyl carbonate) partners is achieved through phosphine addition and π-allyl formation, respectively. Such “two-component catalyst systems” are uncommon.6 Moreover, the use of nucleophilic catalysis as a means of enolate generation in metal-catalyzed cross-coupling is without precedent.5,7 The feasibility of this proposal is borne out by the results reported herein. Upon exposure of mono-enone monoallylic carbonates to tributylphosphine and substoichiometric quantities of Pd(Ph3P)4, efficient conversion to the corresponding cycloallylated products is achieved. This transformation combines the nucleophilic features of the Morita-Baylis-Hillman reaction with the electrophilic features of the Trost-Tsuji reaction (eq 1).
Recently, the present author and Roush disclosed a trialkylphosphine-catalyzed cycloisomerization of electron-deficient 1,5- and 1,6-dienes.4,8,9 This discovery stimulated interest in the design of related transformations potentially developed through variation of the electrophilic partner. In accordance with this goal, and the aforementioned rationale for concomitant activation of latent nucleophilic and electrophilic partners, the following mechanism for catalytic enone cycloallylation was envisioned. In this scenario, catalysis is contingent upon the separate yet concomitant action of organic and metallic promoters (Scheme 1). To assess the feasibility of the proposed transformation, catalytic intramolecular cycloallylation of mono-enone mono-allylic acetate 1a was attempted using tributylphosphine and Pd(Ph3P)4 as nucleophilic and electrophilic activators, respectively. Initial experiments performed in aprotic media using 10 mol % Pd(Ph3P)4 and 50 mol % PBu3 resulted in a poor yield of cycloallylation product 1b (Table 1, entry 1). It was postulated that capture of the metalloπ-allyl intermediate would be facilitated were the lifetime of the transiently generated enolate to be extended through solvation in 7758
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Scheme 1. Proposal: Catalytic Cycloallylation via Concommitant Activation of Latent Nucleophilic and Electrophilic Partners
Table 1. Optimization of the Catalytic Cycloallylation of 1a
entry
R
solvent
(Ph3P)4Pd (mol %)
PBu3 (mol %)
T (°C)
yielda (%)
1 2 3 4 5
COCH3 COCH3 COCH3 CO2CH3 CO2CH3
THF t-BuOH t-BuOH t-BuOH t-BuOH
10 4 4 5 1
50 50 100 100 100
60 30 60 60 60
6 21 67 92 92
a
Isolated yields after purification by silica gel chromatography.
Scheme 2. Synthesis of Mono-enone Mono-allylic Carbonates 1a-8a
the form of hydrogen-bond interactions. Accordingly, the use of tert-butyl alcohol as solvent increased the yield of 1b to 21% at reduced loading of Pd(Ph3P)4 (Table 1, entry 2). To further promote trapping of the metallo-π-allyl, the loading of PBu3 was doubled, which raised the yield of cycloallylation product to 67% (Table 1, entry 3). The preceding experiments were performed using the allylic acetate of 1a, which upon ionization generates acetate ion and, ultimately, acetic acid. It was recognized that the corresponding methyl carbonate would generate methoxide ion upon ionization, potentially facilitating β-elimination of PBu3 in the final step of the catalytic cycle (Scheme 1). Indeed, the allylic carbonate of 1a provides cycloallylation product 1b in 92% yield (Table 1, entry 4). This yield was found to persist at 1% loading of Pd(Ph3P)4 (Table 1, entry 5). Given the preceding result, a concise and modular synthetic route to cycloallylation substrates 1a-8a was sought. Remarkably, 10.1021/ja0301469 CCC: $25.00 © 2003 American Chemical Society
COMMUNICATIONS Table 2. Catalytic Cycloallylation of Mono-enone Mono-allylic Carbonatesa
valent transition-metal complexes.10 Whereas enoate 7a provides only trace quantities of cycloallylation product 7b, the corresponding thioenoate 8a is readily cyclized (Table 2, entry 7). This result is consistent with the enhanced performance of thioenoates in MoritaBaylis-Hillman-type cyclizations11,4b and is remarkable in view of the well-established susceptibility of thioesters to oxidative addition by low-valent palladium.12 Finally, as demonstrated by the catalytic cycloallylation of substrates 9a-11a, six-membered ring formation proceeds smoothly, albeit in diminished yield (Table 2, entries 8-10). In summary, we demonstrate the feasibility of nucleophilic catalysis as a means of enolate generation in metal-catalyzed cross coupling, as evidenced by the development of a catalytic enone cycloallylation methodology. This transformation is achieved through the use of a two-component catalyst system that unites the nucleophilic features of the Morita-Baylis-Hillman reaction with the electrophilic features of the Trost-Tsuji reaction. Future studies will be devoted to the development of related catalytic transformations, including enantioselective variants of the methodology described herein. Acknowledgment. Acknowledgment is made to the Robert A. Welch Foundation (F-1466), the NSF-CAREER program (CHE0090441), the Herman Frasch Foundation (535-HF02), the NIH (RO1 GM65149-01), donors of the Petroleum Research Fund administered by the ACS (34974-G1), the Research Corporation Cottrell Scholar Award (CS0927), the Alfred P. Sloan Foundation, the Camille and Henry Dreyfus Foundation, and Eli Lilly for partial support of this research. Supporting Information Available: Spectral data for all new compounds (1H NMR, 13C NMR, IR, HRMS) (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. References
a Procedure: Tributylphosphine (100 mol %) and Pd(PPh ) (1 mol %) 3 4 were added to a 0.1 M solution of substrate in tert-butyl alcohol, and the reaction was allowed to stir at 60 °C until complete consumption of starting material, at which point the reaction mixture was evaporated onto silica and purified via silica gel chromatography. b Isolated yields were calculated after purification by silica gel chromatography. c 5 mol % of Pd(PPh3)4 was used for this single example. At 1 mol % catalyst loading the yield of 6b was 65%.
exposure of methyl allyl carbonate and 4-penten-1-ol to the secondgeneration Grubb’s catalyst provides the cross-metathesis product in moderate yield. Tandem Moffatt-Swern oxidation-Wittig olefination then affords substrates 1a-8a (Scheme 2). With a set of structurally diverse cycloallylation substrates in hand, the scope of the catalytic cycloallylation was examined. As demonstrated by the catalytic cycloallylation of substrates 1a-6a, aromatic, heteroaromatic and aliphatic enones represent viable reacting partners (Table 2, entries 1-6). The cycloallylation of cyclopropyl substituted enone 6a is noteworthy, as cyclopropanes possessing adjacent π-unsaturation are known to react readily with low-
(1) For a review, see: Jang, H.-Y.; Cauble, D. F.; Huddleston, R. R.; Krische M. J. Acc. Chem. Res. 2003, 36, submitted. (2) For catalytic hydrometallative and carbometallative aldol and Michael cycloreductions, see: (a) Baik, T.-G.; Luis, A.-L.; Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112. (b) Wang, L.-C.; Jang, H.-Y.; Lynch, V.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448. (c) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 15156. (d) Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143. (e) Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110. (3) For catalytic cycloadditions, see: (a) Baik, T.-G.; Wang, L.-C.; Luis, A.L.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 6716. (b) Wang, J.-C.; Ng, S.-S. Michael J. Krische J. Am. Chem. Soc. 2003, 125, 3682. (4) For catalytic cycloisomerizations, see: (a) Wang, L.-C.; Luis, A.-L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402. (b) Agapiou, K.; Krische, M. J. Org. Lett 2003, 5, 1737. (5) For selected reviews, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (b) Consiglio, G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257. (6) For selected examples of two-component catalyst systems, see: (a) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309. (b) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 12702. (7) For catalytic enone alkoxyallylation and hydroallylation, see: (a) Nakamura, H.; Sekido, M.; Ito, M.; Yamamoto, Y. J. Am. Chem. Soc. 1998, 120, 6838. (b) Muraoka, T.; Matsuda, I.; Itoh, K. J. Am. Chem. Soc. 2000, 122, 9552. (8) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404. (9) For a recent review, see: Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811. (10) For reviews, see: (a) Sarel, S. Acc. Chem. Res. 1978, 11, 204. (b) Ohta, T.; Takaya, H. Metal Catalyzed Cycloaddition of Small Ring Compounds. In ComprehensiVe Organic Synthesis; Trost, B., Fleming, I., Eds.; Permagon: Oxford, 1991; Vol. 5, pp 1185-1205. (11) Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4, 3687. (12) See, for example: Fukuyama, T.; Lin, S. C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050.
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